Valproic acid, which is useful as an antiepileptic drug, has been widely administered to treat epilepsy and prevent seizures. However, valproic acid deliquesces only by being left to stand at room temperature because of its high hygroscopicity. Therefore, there is no valproic acid preparation that is applicable to a one-dose pack. Thus, there is a need for development of a preparation that has stability against moisture and does not deliquesce under normal storage conditions.
Known methods for improving the deliquescence of valproic acid include, for example, a method of blending a solid preparation with a non-hygroscopic excipient (JP 2004-521890A), a method of sugar-coating (JP 2006-256961A), a method of film-coating with macromolecular substances (JP 2006-83162A), and a method of packaging with packaging materials having high water vapor barrier properties.
For example, JP 2004-521890A discloses a method of mixing sodium valproate, carbomer, and a non-hygroscopic additive to a homogeneous state and compressing the resulting mixture into tablets, which tablets have properties of absorbing up to 5% by weight of water even when stored at 75% relative humidity for three months.
JP 2006-256961A discloses tablets produced by sugar-coating sodium valproate sequentially with a first layer composed of sucrose soluble in water and organic solvents, a second layer composed of macromolecules and sucrose soluble in water and organic solvents, a third layer composed of sucrose, and a fourth layer composed of macromolecules, sucrose, and the like, which tablets have stability against moisture.
JP 2006-83162A discloses double-coated tablets in which a first coating layer is formed from a coating agent mainly composed of starch and sugar, and a second coating layer is formed thereon from a coating agent mainly composed of macromolecules, which double-coated tablets suppresses the deliquescence of the deliquescent drug contained as an active ingredient.
As a method of packaging with packaging materials having high water vapor barrier properties, the method of protecting a solid preparation from moisture by placing the solid preparation in a PTP (press through pack) sheet laminated with polyvinylidene chloride and sealing the sheet is used in various medicaments.
On the other hand, to prevent patients from forgetting to take prescribed drugs or taking a wrong dose, one-dose packs are now in widespread use at clinical sites and dispensing pharmacies. Taking a plurality of solid preparations to be taken in one dose out of packaging materials such as a PTP sheet and putting them in one package to provide to patients have become predominant.
However, in one-dose packing, each solid preparation will be stored for a long period of time in an automatic packaging machine in a naked state as taken out of a PTP sheet in advance. Therefore, for preparations which have low stability against moisture and contain as an active ingredient valproic acid having deliquescence, it is difficult at present to use a one-dose pack. That is, patients who receive a preparation containing valproic acid as an active ingredient have not gained the advantage of one-dose packs that they improve drug compliance to enhance the therapeutic effect. There is a need for improvement in this regard.
There are methods, as disclosed in JP 2004-521890A, JP 2006-256961A and JP 2006-83162A, for improving the stability against moisture of a preparation containing sodium valproate. However, in these methods, increase in size of a solid preparation due to coating cannot be avoided, making it difficult for patients to ingest. Hence, it is difficult at present to put the preparation into practice. In particular, the method of sugar-coating a solid preparation, as disclosed in JP 2006-256961A, not only requires a long period of time for the process of sugar-coating, but also has a problem in that, under high humidity, it exhibits poor moisture barrier properties and cannot suppress deliquescence and liquefaction. Further, the double-coated tablet disclosed in JP 2006-83162A requires strict control of the production conditions because it requires multiple coating steps, so that, in view of both production time and production cost, it is difficult to apply it to a preparation containing sodium valproate.
Thus, it could be helpful to provide a coated solid preparation applicable to a one-dose pack, wherein, even when the preparation is in an unpacked state, the stability against moisture of valproic acid or a pharmacologically acceptable salt thereof contained therein is maintained and the deliquescence is suppressed.